HIV-2287 has been proven to cause a rapid and consistent disease course in the Macaca nemestrina. We have developed a set of molecular clones with variable cytopathic effects to macaque peripheral blood mononuclear cells in tissue culture. The availability of these molecular clones allows for the determination of the viral genes that are directly involved in pathogenesis. Two macaques were assigned to be inoculated. One macaque was inoculated with a set of molecular cloned viruses that replicated to high titers in culture. This macaque became infected with the virus and showed a significant immune response as measured by antibody EIA and Western blot; however, there has been no effect on the CD4+ cell population, or other signs of disease. Another macaque was inoculated with plasma isolates that were determined to have a clonal relationship based on the envelope homogeneity. This macaque developed the acute CD4 depletion that is the typical response following inoculation with HIV-2287 wild-type virus. Additional studies are planned as molecular clones become available.